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A Study of Ad-RTS-hIL-12 + Veledimex in Pediatric Subjects With Brain Tumors or DIPG

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ClinicalTrials.gov Identifier: NCT03330197
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : June 26, 2018
Sponsor:
Information provided by (Responsible Party):
Ziopharm

Brief Summary:

This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human IL-12. IL-12 is a protein that can improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.

The main purpose of this study is to evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex in the pediatric population.


Condition or disease Intervention/treatment Phase
Pediatric Brain Tumor Diffuse Intrinsic Pontine Glioma Biological: Ad-RTS-hIL-12 Drug: oral veledimex Phase 1

Detailed Description:

Eligible patients will be stratified to one of two arms, according to clinical indication for tumor resection. Pediatric patients who are scheduled for craniotomy and tumor resection will receive one dose of veledimex before the resection procedure. Ad-RTS-hIL-12 will be administered by free-hand injection. Patients will continue on oral veledimex for 14 days.

Pediatric patients with diffuse intrinsic pontine glioma (DIPG) will receive Ad-RTS-hIL-12 by stereotactic injection and then will continue on oral veledimex for 14 days.

The study is divided into three periods: the screening period, the treatment period and the follow-up period.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: There will be two groups of patients enrolled.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the Activator Ligand Veledimex in Pediatric Brain Tumor Subjects
Actual Study Start Date : September 26, 2017
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
Experimental: Ad-RTS-hIL-12 +veledimex
Intratumoral Ad-RTS-hIL-12 injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors (supratentorial tumors and DIPG)
Biological: Ad-RTS-hIL-12
2.0 x 10^11 viral particles (vp) per injection, one intratumoral injection of Ad-RTS-hIL-12

Drug: oral veledimex
2 dose levels (10mg/day, 20mg/day) 14 (or 15) oral daily doses of veledimex




Primary Outcome Measures :
  1. The safety and tolerability of intratumoral Ad-RTS-hIL-12 and veledimex as measured by dose limiting toxicities and compliance. [ Time Frame: From Day 0 through 30 days after the last dose of veledimex ]

Secondary Outcome Measures :
  1. To measure the veledimex in blood and brain tumor by using the LC-MS method [ Time Frame: From Day 0 through 30 days after the last dose of veledimex ]
  2. Evaluate preliminary efficacy of Ad-RTS-hIL-12 and veledimex by assessing survival and tumor response rates [ Time Frame: 2 Years ]
  3. Measure immune response of Ad-RTS-hIL-12 and veledimex by a quantitative multiplex immunoassay for determination of IL-12 and IFNg levels [ Time Frame: 28 Days ]
  4. Subjects with Ad-RTS-hIL-12 and veledimex related adverse events will be assessed for safety by CTCAE v4.0 [ Time Frame: 2 Years ]


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female subjects ≤ 21 years-of-age with the demonstrated ability to swallow capsules whole and who are willing to provide access to previously obtained biopsy results
  2. Provision of written informed consent and assent, when applicable, for tumor resection, stereotactic surgery, tumor biopsy, sample collection, and/or treatment with study drug prior to undergoing any study-specific procedures
  3. Arm 1: Evidence of recurrent or progressive supratentorial tumor, which has shown a > 25% increase in bi dimensional measurements by MRI or is refractory with significant neuro deterioration that is not otherwise explained with no known curative therapy.

    Arm 2: Clinical presentation of DIPG and compatible MRI with approximately 2/3 of the pons included. Subject should be ≥ 2 weeks and ≤ 10 weeks post standard focal radiotherapy (ie, dose of 5400 to 5960 cGy and maximum dexamethasone of 1 mg/m2/day)

  4. At the time of registration, subjects must have recovered from the toxic effects of previous treatments, as determined by the treating physician.

    1. Targeted agents, including small-molecular tyrosine kinase inhibitors: 2 weeks
    2. Other cytotoxic agents: 3 weeks
    3. Nitrosoureas: 6 weeks
    4. Monoclonal antibody immunotherapies (eg, PD-1, CTLA-4): 6 weeks
    5. Vaccine-based and/or viral therapy: 3 months
  5. On a stable or decreasing dose of dexamethasone for the previous 7 days
  6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment
  7. Have age-appropriate functional performance:

    1. Lansky score ≥ 50 or
    2. Karnofsky score > 50 or
    3. Eastern Cooperative Oncology Group (ECOG) score ≤ 2
  8. Have adequate bone marrow reserves and liver and kidney function, as assessed by the following laboratory requirements:

    1. Hemoglobin ≥ 8 g/L
    2. Absolute lymphocyte count ≥ 500/mm3
    3. Absolute neutrophil count ≥ 1000/mm3
    4. Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth factors)
    5. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age
    6. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for age
    7. Total bilirubin < 1.5 x ULN for age
    8. International normalized ratio (INR) and activated thromboplastin time within normal institutional limits
  9. Male and female subjects of childbearing potential must agree to use a highly reliable method of birth control (expected failure rate < 1% per year) from the Screening Visit through 28 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

  1. Radiotherapy treatment prior to the first veledimex dose:

    1. Focal radiation ≤ 4 weeks
    2. Whole-brain radiation ≤ 6 weeks
    3. Cranio-spinal radiation ≤ 12 weeks NOTE: Subjects in Arm 2 (ie, with DIPG) must be ≥ 2 weeks and ≤ 10 weeks after standard focal radiotherapy (dose of 5400 to 5960 cGy and maximum dexamethasone of 1 mg/m2/day)
  2. Subjects with clinically significant increased intracranial pressure (eg, impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures
  3. Subjects whose body surface area (BSA) would expose them to < 75% or > 125% of the target dose
  4. Known immunosuppressive disease, autoimmune condition, and/or chronic viral infection (eg, human immunodeficiency virus [HIV], hepatitis)
  5. Use of systemic antibacterial, antifungal, or antiviral medications for the treatment of acute clinically significant infection within 2 weeks of first veledimex dose. Concomitant therapy for chronic infections is not allowed. Subjects must be afebrile prior to Ad-RTS-hIL-12 injection; only prophylactic antibiotic use is allowed perioperatively
  6. Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first dose of study drug
  7. Other concurrent clinically active malignant disease, requiring treatment
  8. Nursing or pregnant females
  9. Prior exposure to veledimex
  10. Use of medications that induce, inhibit, or are substrates of cytochrome p450 (CYP450) 3A4 within 7 days prior to veledimex
  11. Use of heparin or acetylsalicylic acid (ASA)
  12. Presence of any contraindication for a neurosurgical procedure
  13. Unstable or clinically significant concurrent medical condition

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03330197


Contacts
Contact: Rich MacKenna 617-259-1976 rmackenna@ziopharm.com
Contact: Jill Buck 617-259-1750 jbuck@ziopharm.com

Locations
United States, California
University of California San Francisco, Benioff Children's Hospital Recruiting
San Francisco, California, United States, 94158
Contact: Shelby Gripe    415-476-3838    Shelby.Gripe@ucsf.edu   
United States, Illinois
Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Debra Tice    312-227-4090    dtice@luriechildrens.org   
United States, Massachusetts
Dana- Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Susan Chi, MD    617-632-5376    susan_chi@dfci.harvard.edu   
Sponsors and Collaborators
Ziopharm
Investigators
Study Director: Francois Lebel, MD ZIOPHARM Oncology, Inc.

Responsible Party: Ziopharm
ClinicalTrials.gov Identifier: NCT03330197     History of Changes
Other Study ID Numbers: ATI001-103
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: June 26, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ziopharm:
DIPG
Glioblastoma
Anaplastic Astrocytoma
High Grade Glioma (HGG) Not Otherwise Specified (NOS)
Supratentorial Tumor NOS

Additional relevant MeSH terms:
Glioma
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases